The broad, long-term objective of this application is to develop intermolecular double-quantum coherence (iDQC) MR imaging with particular focus on applications in the brain. This is based on the primary hypothesis that iDQC provides novel and unique imaging contrast which is relevant to and potentially useful in a wide variety of important MRI applications, including brain fMRI, detection of hypoxia in tumors, diffusion-weighted imaging, and characterization of trabecular bones. However, owing to the early nature of the technique, we believe that it is crucial to gain a better understanding of fundamentals of iDQC imaging contrast mechanisms, and to determine the key factors for imaging optimization before applications of iDQC imaging become practical. The specific aims of this proposal are therefore to quantify the novel iDQC image contrast in terms of intrinsic parameters (including relaxation, diffusion, sensitivity to magnetic susceptibility distributions, and dependence of iDQC signals on microstructures) and experimental parameters (field strength, pulse timing, coherence selection, detection method). These aims are achieved via research designs and methods in development of optimal iDQC imaging techniques with high SNR and unique contrast characteristics, guided by theoretical analyses and computer simulations, and validated with measurements in phantoms and rat brains at 1.5 9.4 and 14T, and brains of normal human volunteers at 1.5T. Our pulse sequence optimization will be approached from signal excitation, signal detection, and image post-processing, based on the unique characteristics of iDQC signals. The outcome of this study should lead to quantitation of essential factors for iDQC imaging contrast, and much improved imaging techniques applicable for a variety of novel applications at different field strengths.